Efficacy and Safety of Zanubrutinib Plus Tislelizumab for Treatment of Patients With Richter Transformation

Learn more about:
Related Clinical Trial
Safety & Efficacy Study of Epcoritamab in Subjects With R/R Chronic Lymphocytic Leukemia and Richter’s Syndrome ALX148, Rituximab and Lenalidomide for the Treatment of Indolent and Aggressive B-cell Non-Hodgkin Lymphoma R-EPOCH in Combination With Ibrutinib for Patients With Classical RT of CLL Phase 1 Study VIP152 in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia or Richter Syndrome A Study to Evaluate the Efficacy and Safety of Obinutuzumab, Ibrutinib, and Venetoclax in Patients With Richter’s Syndrome; Study of Cosibelimab in Subjects With Relapsed or Refractory Lymphoma CD19-Directed CAR-T Cell Therapy for the Treatment of Relapsed/Refractory B Cell Malignancies Study of TG-1801 Alone or in Combination With Ublituximab in Subjects With B-Cell Lymphoma or Chronic Lymphocytic Leukemia Study of Oral Administration of LP-118 in Patients With Relapsed or Refractory NHL, RT, MM, T-PLL, Acute Leukemia (AML, ALL), MDS, MDS/MPN, and MF Ipilimumab, Ibrutinib, and Nivolumab for the Treatment of Chronic Lymphocytic Leukemia and Richter Transformation Polatuzumab Vedotin in Combination With Chemotherapy in Subjects With Richter’s Transformation Autologous Stem Cell Transplant Followed by Polatuzumab Vedotin in Patients With B-cell Non-Hodgkin and Hodgkin Lymphoma Venetoclax in Combination With Ublituximab and Umbralisib (TGR-1202) in Patients With Relapsed or Refractory CLL/SLL Ex Vivo-activated Autologous Lymph Node Lymphocytes in Treating Patients With Chronic Lymphocytic Leukemia Allogeneic Stem Cell Transplant for CLL Study of a Triple Combination Therapy, DTRM-555, in Patients With R/R CLL or R/R Non-Hodgkin’s Lymphomas Atezolizumab, Gemcitabine, Oxaliplatin, and Rituximab in Treating Patients With Relapsed or Refractory Transformed Diffuse Large B-Cell Lymphoma Atezolizumab, Obinutuzumab, and Venetoclax in Treating Patients With Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Relapsed or Refractory Richter Syndrome Duvelisib and Nivolumab in Treating Patients With Richter Syndrome or Transformed Follicular Lymphoma Sotrastaurin Acetate in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia, Prolymphocytic Leukemia, or Richter’s Transformation Registry of the German CLL Study Group Nivolumab and Ibrutinib in Treating Patients With Relapsed, Refractory, or High-Risk Untreated Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Richter Transformation ACP-196 (Acalabrutinib), a Novel Bruton Tyrosine Kinase (Btk) Inhibitor, for Treatment of Chronic Lymphocytic Leukemia A Study of Acalabrutinib and Vistusertib in Subjects With Relapsed/Refractory B-cell Malignancies Study of Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone (CHOP) With Ofatumumab in Patients With Richter’s Syndrome PNT2258 for Treatment of Patients With Richter’s Transformation (Brighton) Study of Immunotherapy in Combination With Ublituximab and Umbralisib in Patients With Relapsed-refractory CLL or Richter’s Transformation Efficacy and Safety of Zanubrutinib Plus Tislelizumab for Treatment of Patients With Richter Transformation BLINAtumomab After R-CHOP Debulking Therapy for Patients With Richter Transformation Oxaliplatin, Fludarabine, Cytarabine, and Rituximab in Patients With Richter’s Transformation and Leukemias Obinutuzumab Containing Conditioning Regimen for Patients With Poor Risk CLL or Richter`s Transformation Requiring Allogeneic Stem Cell Transplantation Study of Pembrolizumab (MK-3475) in Participants With Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma or Relapsed or Refractory Richter Syndrome (MK-3475-170/KEYNOTE-170) Duvelisib and Venetoclax in Relapsed or Refractory CLL or SLL or RS Study of Blinatumomab in Richter Transformation Genomic and Proteomic Study of Richter Syndrome (CGPSR) CRC043: A Phase II Study of Venetoclax in Combination With Dose-adjusted EPOCH-R for Patients With Richter’s Syndrome Study of Ibrutinib & Obinutuzumab With/Without CHOP for Richter’s Transformation or Richter’s Syndrome Patients Obinutuzumab, High Dose Methylprednisolone (HDMP), and Lenalidomide for the Treatment of Patients With Richter’s Syndrome A Trial of CHOP-R Therapy, With or Without Acalabrutinib, in Patients With Newly Diagnosed Richter’s Syndrome Selinexor in Initial or Refractory and/or Relapsed Richter’s Transformation

Brief Title

Efficacy and Safety of Zanubrutinib Plus Tislelizumab for Treatment of Patients With Richter Transformation

Official Title

A Prospective, Open-label, Multicenter Phase-II Trial to Evaluate the Efficacy and Safety of Zanubrutinib (BGB-3111), a BTK Inhibitor, Plus Tislelizumab (BGB-A317), a PD1 Inhibitor, for Treatment of Patients With Richter Transformation

Brief Summary

      The aim of the CLL-RT1 trial is to evaluate the efficacy and safety of zanubrutinib
      (BGB-3111), a BTK inhibitor plus tislelizumab (BGB-A317), a PD1 inhibitor for treatment of
      patients with Richter Transformation

Detailed Description

      Richter Transformation (RT) remains one of the biggest challenges in the treatment and
      management of CLL. While considerable progress has been made in the treatment of CLL, the
      prognosis of CLL patients with malignant disease transformation still is very poor and
      reported median OS is between 6 to 8 months. Conventional approaches with chemo- and
      chemoimmunotherapy have largely failed to improve response rates in RT patients. However, as
      the established treatment approach for de-novo Diffuse Large B Cell Lymphoma (DLBCL) is
      chemoimmunotherapy with a combination of Rituximab, Cyclophosphamid, Hydroxydaunorubicin,
      Vincristin and Prednisolon (R-CHOP), this has become the most commonly used regimen for lack
      of alternative strategies, despite poor efficacy. Patients being fit enough for allogeneic
      transplantation are undergoing this procedure after induction with R-CHOP. However, the
      majority of patients are not suitable for transplantation and relapse quickly. Hence, there
      is urgent need to improve therapy of RT by testing new compounds and combinations for
      treatment of this disease. Based on the available preclinical and preliminary clinical data
      on checkpoint inhibition plus Bruton's tyrosine (BTK) inhibition, the current trial will
      systematically assess the safety and toxicity of tislelizumab, a programmed cell death
      protein 1 (PD-1) inhibitor, plus zanubrutinib, a BTK inhibitor in patients with RT.

Study Phase

Phase 2

Study Type


Primary Outcome

Overall response rate (ORR) after induction therapy according to the refined Lugano Classification (Cheson et al, 2016)

Secondary Outcome

 ORR after induction therapy according to the IWCLL criteria (Hallek et al, 2018)


Richter Transformation



Study Arms / Comparison Groups

 Tislelizumab + Zanubrutinib
Description:  Induction: 6 cycles (q21d) of Tislelizumab + Zanubrutinib
Consolidation: 6 cycles (q21d) of Tislelizumab + Zanubrutinib
Maintenance: Patients with response to therapy continue to take Tislelizumab + Zanubrutinib (Q3W) until disease progression, non-tolerance or when receiving allogeneic stem cell transplantation (SCT) for consolidation


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

February 19, 2020

Completion Date

June 2023

Primary Completion Date

August 2022

Eligibility Criteria

        Inclusion Criteria:

          1. Confirmed diagnosis of CLL according to iwCLL criteria (Hallek et al, 2018)

          2. Confirmed histopathological diagnosis of RT

          3. Creatinine clearance ≥30ml/min calculated according to the modified formula of
             Cockcroft and Gault or directly measured with 24hr urine collection

          4. Adequate liver function as indicated by a total bilirubin ≤ 2x, AST/ALT ≤ 2.5 x the
             institutional ULN value, unless directly attributable to the patient's CLL/RT or to
             Gilbert's Syndrome, in which case a max. total bilirubin ≤ 4 x and AST/ALT ≤ 5 x the
             institutional ULN value are required

          5. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative;
             patients positive for anti-HBc may be included if PCR for HBV DNA is negative and
             HBV-DNA PCR is performed every two months until 2 months after last dose of
             zanubrutinib), negative testing for hepatitis-C RNA and negative HIV test within 6
             weeks prior to registration

          6. Age at least 18 years

          7. ECOG performance status 0-2, ECOG 3 is only permitted if related to CLL or RT (e.g.
             due to anaemia or severe constitutional symptoms)

          8. Life expectancy ≥ 6 months

          9. Ability and willingness to provide written informed consent and to adhere to the study
             visit schedule and other protocol requirements

        Exclusion Criteria:

          1. Patients who did not respond to previous line of RT therapy (i.e. primary progressive

          2. Patients with more than one prior line of RT therapy

          3. Allogenic stem cell transplantation within the last 100 days or signs of active
             graft-versus-host disease (GVHD) after prior allogeneic stem cell transplantation
             within any time

          4. Patients with confirmed progressive multifocal leukoencephalopathy (PML)

          5. Uncontrolled autoimmune condition

          6. Malignancies other than CLL currently requiring systemic therapies

          7. Active infection currently requiring systemic treatment

          8. Any comorbidity or organ system impairment rated with a Cumulative Illness Rating
             Scale (CIRS) score of 4, excluding the eyes/ears/nose/throat/larynx organ system, or
             any other life-threatening illness, medical condition or organ system dysfunction that
             - in the investigator´s opinion could comprise the patients safety or interfere with
             the absorption or metabolism of the study drugs

          9. Requirement of therapy with strong CYP3A4 inhibitors/inducers

         10. Requirement of therapy with phenprocoumon or other vitamin K antagonists.

         11. Use of investigational agents, e.g. monoclonal antibodies or other experimental drugs
             within clinical trials, which might interfere with the study drug within 28 days (or 5
             times half-life [t1/2] of the compound, whichever is longer) prior to registration

         12. Known hypersensitivity to tislelizumab, zanubrutinib or any of the excipients

         13. Pregnant women and nursing mothers (a negative pregnancy test is required for all
             women of childbearing potential within 7 days before start of treatment)

         14. Fertile men or women of childbearing potential unless:

               -  surgically sterile or ≥ 2 years after the onset of menopause, or

               -  willing to use two methods of reliable contraception including one highly
                  effective contraceptive method (Pearl Index <1) and one additional effective
                  (barrier) method during study treatment and for 12 months after the end of study

         15. Vaccination with a live vaccine <28 days prior to randomization

         16. Legal incapacity

         17. Prisoners or subjects who are institutionalized by regulatory or court order

         18. Persons who are in dependence to the sponsor or an investigator




18 Years - N/A

Accepts Healthy Volunteers



Barbara Eichhorst, Prof., +4922147888220, [email protected]

Location Countries


Location Countries


Administrative Informations



Organization ID


Responsible Party


Study Sponsor

German CLL Study Group

Study Sponsor

Barbara Eichhorst, Prof., Principal Investigator, Department I of Internal Medicine, University Hospital Cologne

Verification Date

March 2022